This Career Development Award proposal is designed to allow the candidate to develop the skills needed to become an outstanding investigator in the translational science of ischemic stroke treatment, and ultrasound-enhanced thrombolysis (UET). Stroke is a major medical problem in the U.S. and a leading cause of death and disability. Currently, the only FDA approved therapy is the administration of tissue plasminogen activator (tPA) within 3 hours of stroke onset. There are many contraindications and side effects to this treatment including intra-cerebral hemorrhage (ICH). Therefore, there is great interest in adjunctive therapies such as UET, GP llb-llla inhibitors, ultrasound-assisted targeted drug delivery agents, and hypothermia that may improve stroke treatment and possibly reduce side effects of thrombolytic therapy. Improved effectiveness and/or greater safety in the use of thrombolytic therapy would provide a great benefit to the public health, as the incidence of ischemic stroke is increasing as the overall population ages. The objectives of this proposal are to 1) develop expertise and didactic knowledge in neuroscience, ultrasound and microscopic imaging, 2) gain familiarity with the clinical treatment of acute stroke, and (3) study the effects of adjunctive therapies on tPA thrombolysis in an in-vitro human clot model. The candidate proposes a 5-year career development program with contributors funded in the area of stroke research. The contributors to this proposal are respected experts in Neurology, Biochemistry and Biomedical Engineering, which are areas directly relevant to the proposal. The plan focuses on enhancing the knowledge required to implement basic and translational research in ultrasound-assisted thrombolysis, ultrasound contrast agents and hypothermia as potential adjunctive treatments for stroke. This includes coursework, independent study and specific clinical training rotations. Training in the responsible conduct of research and mentored experiences in the clinical treatment of acute ischemic stroke are planned. The proposed research will examine the effects of GP llb-llla inhibitors, ultrasound contrast agents and hypothermia on ultrasound enhanced tPA thrombolysis. A unique microscopic visualization technique will be employed to observe in-vitro human clot dissolution during lytic treatment in real-time. This innovative technique allows the direct measurement of clot size while it undergoes lysis. The efficacy of adjunctive therapies will be assessed via this microscopic quantification of clot dissolution. The overall hypothesis is that ultrasound improves the thrombolytic efficacy of tPA with or without adjunctive therapies. Such data would be of tremendous use in planning future in-vitro, in-vivo and clinical trials studying these adjunctive therapies. The results of this work could easily be taken from "bench to bedside" by virtue of the candidate's ongoing collaboration with Greater Cincinnati/Northern Kentucky stroke team. [unreadable] [unreadable] [unreadable]